Over the years the framework for our research efforts has been formed from our concepts of five proven or potential causes of the brain damage produced by head injury (mechanical damage, hemorrhage, ischemia, brain swelling, toxic substances). Our studies of cerebral blood flow, metabolism, and intracranial pressure in severely head injured patients emphasize the importance of ischemia and brain swelling. In some patients both blood flow and metabolism are reduced, whereas in others, especially children, blood flow is normal or increased in the face of decreased metabolism. This hyperemic state can lead to severe and sometimes fatal brain swelling. A major goal of this program is to define the incidence, etiology and proper therapy for cerebral hyperemia. There is ample evidence that ischemia is a common cause of irreversible brain damage and death in head injured patients. In animal models, we have found evidence that following an ischemic insult that ultimately leads to death of the tissue, there is secondary deterioration of the energy state of the brain following restoration of normal circulation. The results imply that the brain is not irreversibly damaged by the ischemic insult per se, but is destroyed by factors that operate during the period of recirculation. Finally, we have developed a model of acceleration head injury in the monkey in which we have simulated nearly all of the pathology of human head injury. The model lends itself well to study of the five causes of brain damage produced by head injury.